Cystic fibrosis (CF) is a highly variable but inevitably fatal disorder caused by mutations in the CFTR gene. The disease manifests as progressive obstructive lung disease due to abnormalities in airway surface liquid and chronic malnutrition due to exocrine pancreatic insufficiency. Survival of CF patients is highly correlated with the severity of lung disease and degree of malnutrition. Although CFTR genotype is predictive of some aspects of the CF phenotype, we are still trying to understand the underlying causes of variation in traits that have significant effect upon survival. To this end, we initiated the CF Twin and Sibling Study to determine the degree to which genetic factors contribute to trait variability independent of CFTR genotype. Analysis of over 600 families with twins or siblings affected with CF reveal that modifier genes underlie variation in lung disease severity, as measured by pulmonary function testing (heritability estimates 0.6-0.8) and malnutrition, as measured by nutritional status (heritability estimates 0.5-0.9). A 10cM short tandem repeat scan of a subset of families has identified several regions of suggestive linkage (LOD scores >2.0) for these traits. Intriguingly, several of the linkage regions for lung function and nutritional status coincide, consistent with the clinical observation of a close relationship between these two quantitative traits. The overall goal of this application is to identify the genes that modify lung function and nutritional status in CF patients. This goal will be achieved by pursuit of the following aims: Aim 1. To confirm and refine regions of linkage for lung function and nutritional status. Aim 2. To identify genetic variants within linkage peaks that contribute to variance in lung function and/or growth in CF patients. Aim 3. To refine estimates of the contribution of genetic and non-genetic factors to variation in CF phenotypes by prospective longitudinal analysis.